Previous studies correlate the sequential acquisition of anchorage independent clonogenicity, tumorigenesis, karyotypic and immunophenotypic divergence with prognosis to suggest a model of glioma progression.Transforming growth factor type-beta (TGFbeta) demonstrates autocrine growth inhibition among the near diploid gliomas, both low-grade and malignant. This inhibitory effect may be mediated through down regulation of c-myc via interaction with the retinoblastoma susceptibility gene product and/or the tumor suppressor gene (TSG) product, p53. In contrast, TGFbeta is an autocrine mitogen among the highest grade, the hyperdiploid glioblastomas (HD-GBM). TGFbeta-stimulation is temporally associated with induction of the platelet derived growth factor -A (PDGF-A) and/or c- sis genes (1-3, APPENDIX A I-III). This application hypothesizes (A) that TGFbeta stimulation of mitogenesis may be indirect through the autocrine induction of PDGF-A, c-sis and/or PDGF receptor (PDGF-R). (B) This may emerge as its dominant effect when the mediating elements of TGFbeta inhibition are lost among the HD-GBM, due to acquired mutations and/or loss of a TSG. Preliminary data implicates p53 as a possible candidate.The correlation between increasing anaplasia, karyotypic divergence and conversion of TGFbeta auto-regulation suggests that the contribution of TSG mutation/loss is testable within a model of glioma progression. (I) To investigate the possible autocrine role of PDGF peptides among the TGFbeta stimulated HD-GBM, anti- PDGF neutralizing antibodies are used to prevent TGFbeta induced mitogenesis. Differential TGFbeta modulation of PDGF-A, c-sis and PDGF-R expression is examined between the TGFbeta inhibited v.-stimulated gliomas to identify whether this is an important level of TGFbeta control. (II) Endogenous p53 among the gliomas is examined for mutations by PCR amplification and sequencing. To investigate whether or not p53 mutations alter TGFbeta auto-regulation, transfection of a temperature dependent murine mutant p53 gene is proposed into representative TGFbeta inhibited gliomas and TGFbeta stimulated HD-GBM. The transfected cultures are tested for conversion of TGFbeta auto-regulation, PDGF modulation and growth kinetics, under permissive and non-permissive conditions. (III) Attempt to substantiate this association by the transfection of an established human p53 mutant into a TGFbeta inhibited glioma. Conversely, transfect human p53 wild type into an aggressive HD-GBM lacking p53. These transfectants are to be investigated for conversion of TGFbeta auto-regulation, PDGF modulation and growth kinetics.